N6-Methyladenosine: a conformational marker that regulates the substrate specificity of human demethylases FTO and ALKBH5
N6-Methyladenosine (m6A) is currently one of the most intensively studied post-transcriptional modifications in RNA. Due to its critical role in epigenetics and physiological links to several human diseases, it is also of tremendous biological and medical interest. The m6A mark is dynamically revers...
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| Format: | Journal Article |
| Language: | English |
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2018
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| Online Access: | https://hdl.handle.net/10356/87480 http://hdl.handle.net/10220/46698 |
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| author | Zou, Shui Toh, Joel D. W. Wong, Kendra H. Q. Gao, Yong-Gui Hong, Wanjin Woon, Esther C. Y. |
| author2 | School of Biological Sciences |
| author_facet | School of Biological Sciences Zou, Shui Toh, Joel D. W. Wong, Kendra H. Q. Gao, Yong-Gui Hong, Wanjin Woon, Esther C. Y. |
| author_sort | Zou, Shui |
| collection | NTU |
| description | N6-Methyladenosine (m6A) is currently one of the most intensively studied post-transcriptional modifications in RNA. Due to its critical role in epigenetics and physiological links to several human diseases, it is also of tremendous biological and medical interest. The m6A mark is dynamically reversed by human demethylases FTO and ALKBH5, however the mechanism by which these enzymes selectively recognise their target transcripts remains unclear. Here, we report combined biophysical and biochemical studies on the specificity determinants of m6A demethylases, which led to the identification of an m6A-mediated substrate discrimination mechanism. Our results reveal that m6A itself serves as a ‘conformational marker’, which induces different conformational outcomes in RNAs depending on sequence context. This critically impacts its interactions with several m6A-recognising proteins, including FTO and ALKBH5. Remarkably, through the RNA-remodelling effects of m6A, the demethylases were able to discriminate substrates with very similar nucleotide sequences. Our findings provide novel insights into the biological functions of m6A modifications. The mechanism identified in this work is likely of significance to other m6A-recognising proteins. |
| first_indexed | 2025-02-19T03:53:33Z |
| format | Journal Article |
| id | ntu-10356/87480 |
| institution | Nanyang Technological University |
| language | English |
| last_indexed | 2025-02-19T03:53:33Z |
| publishDate | 2018 |
| record_format | dspace |
| spelling | ntu-10356/874802023-02-28T17:01:44Z N6-Methyladenosine: a conformational marker that regulates the substrate specificity of human demethylases FTO and ALKBH5 Zou, Shui Toh, Joel D. W. Wong, Kendra H. Q. Gao, Yong-Gui Hong, Wanjin Woon, Esther C. Y. School of Biological Sciences Protein Conformation Demethylation DRNTU::Science::Biological sciences N6-Methyladenosine (m6A) is currently one of the most intensively studied post-transcriptional modifications in RNA. Due to its critical role in epigenetics and physiological links to several human diseases, it is also of tremendous biological and medical interest. The m6A mark is dynamically reversed by human demethylases FTO and ALKBH5, however the mechanism by which these enzymes selectively recognise their target transcripts remains unclear. Here, we report combined biophysical and biochemical studies on the specificity determinants of m6A demethylases, which led to the identification of an m6A-mediated substrate discrimination mechanism. Our results reveal that m6A itself serves as a ‘conformational marker’, which induces different conformational outcomes in RNAs depending on sequence context. This critically impacts its interactions with several m6A-recognising proteins, including FTO and ALKBH5. Remarkably, through the RNA-remodelling effects of m6A, the demethylases were able to discriminate substrates with very similar nucleotide sequences. Our findings provide novel insights into the biological functions of m6A modifications. The mechanism identified in this work is likely of significance to other m6A-recognising proteins. NRF (Natl Research Foundation, S’pore) MOE (Min. of Education, S’pore) NMRC (Natl Medical Research Council, S’pore) MOH (Min. of Health, S’pore) Published version 2018-11-26T02:07:05Z 2019-12-06T16:42:48Z 2018-11-26T02:07:05Z 2019-12-06T16:42:48Z 2016 Journal Article Zou, S., Toh, J. D. W., Wong, K. H. Q., Gao, Y.-G., Hong, W., & Woon, E. C. Y. (2016). N6-Methyladenosine: a conformational marker that regulates the substrate specificity of human demethylases FTO and ALKBH5. Scientific Reports, 6, 25677-. doi:10.1038/srep25677. https://hdl.handle.net/10356/87480 http://hdl.handle.net/10220/46698 10.1038/srep25677 27156733 en Scientific Reports © 2016 The Authors (Nature Publishing Group). This work is licensed under a Creative Commons Attribution 4.0 International License. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in the credit line; if the material is not included under the Creative Commons license, users will need to obtain permission from the license holder to reproduce the material. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/ 12 p. application/pdf |
| spellingShingle | Protein Conformation Demethylation DRNTU::Science::Biological sciences Zou, Shui Toh, Joel D. W. Wong, Kendra H. Q. Gao, Yong-Gui Hong, Wanjin Woon, Esther C. Y. N6-Methyladenosine: a conformational marker that regulates the substrate specificity of human demethylases FTO and ALKBH5 |
| title | N6-Methyladenosine: a conformational marker that regulates the substrate specificity of human demethylases FTO and ALKBH5 |
| title_full | N6-Methyladenosine: a conformational marker that regulates the substrate specificity of human demethylases FTO and ALKBH5 |
| title_fullStr | N6-Methyladenosine: a conformational marker that regulates the substrate specificity of human demethylases FTO and ALKBH5 |
| title_full_unstemmed | N6-Methyladenosine: a conformational marker that regulates the substrate specificity of human demethylases FTO and ALKBH5 |
| title_short | N6-Methyladenosine: a conformational marker that regulates the substrate specificity of human demethylases FTO and ALKBH5 |
| title_sort | n6 methyladenosine a conformational marker that regulates the substrate specificity of human demethylases fto and alkbh5 |
| topic | Protein Conformation Demethylation DRNTU::Science::Biological sciences |
| url | https://hdl.handle.net/10356/87480 http://hdl.handle.net/10220/46698 |
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